Available vehicles for the administration of hydrophobic drugs, such as water-insoluble or low water soluble compounds often result in undesirable side-effects. Such undesired side-effects include hemolysis, thrombophlebitis or at times, blood coagulation. Liposomes and oil-in-water emulsions have been employed as potential carriers for these hydrophobic drugs that may reduce such undesirable side-effects. However, there remain significant problems associated with stability and drug loading capacity associated with the use of these delivery systems.
Implantable medical devices or compositions for the delivery of biologically active agents are known in the art. However, the placement of metal or polymeric devices in the body are useful for treating a variety of medical conditions, but often results in complications. These complications may include increased risk of infection, inflammation, fibrous encapsulation, and potentially a wound healing response resulting in hyperplasia and restenosis.
One approach to reducing these adverse affects is to provide biocompatible implantable devices. Several implantable medical devices capable of delivering biologically active agents through releasing coatings are known in the art, including U.S. Pat. No. 4,916,193; U.S. Pat. No. 4,994,071; U.S. Pat. No. 5,221,698 and U.S. Pat. No. 5,304,121. U.S. Pat. No. 4,970,298 describes a biodegradable collagen matrix suitable for use as a wound implant. The matrix is formed by freeze drying an aqueous dispersion containing collagen, cross-linking the collagen via two cross-linking steps and freeze-drying the cross-linked matrix. The matrix may also contain hyaluronic acid and fibronectin.
EP-A-0274898 describes an absorbable implant material having an open cell, foam-like structure and formed from resorbable polyesters, such as poly-p-dioxanone, other polyhydroxycarboxylic acids, polylactides or polyglycolides. JP-A-03023864 describes a wound implant material comprising a collagen sponge matrix reinforced with fibers of poly-L-lactic acid. The collagen sponge matrix is formed by freeze drying a solution of porcine atherocollagen. EP-A-0562862 describes bioabsorbable wound implant materials that are composites comprising a collagen sponge matrix having embedded therein oriented substructures of solid collagen fibers, films or flakes. The substructures reinforce the collagen sponge and also provide a scaffold for directional cellular migration into the implant.
It is well known that the water insolubility of a number of important drugs, such as amphotericin B, phenyloin, miconazole, cyclosporin, diazepam and etoposide, makes their formulation for administration, such as by intravenous application, particularly difficult. These drugs, for example, are currently marketed in cosolvent systems such as polyethylene glycol or propylene glycol-ethanol-benzyl alcohol mixtures. However severe toxicity problems, such as thrombophlebitis, have been observed with injectable formulations of drugs dissolved in cosolvents. Alternatives to cosolvent systems are micellar solutions or emulsions; however, the presence of toxic surfactants in those systems makes them undesirable for intravenous administration. Many pharmaceutically useful compounds have limited solubility in physiological fluids. Delivery of such compounds presents a formulation challenge and often requires use of hydrophobic carriers which often present undesirable side effects when introduced in contact with the body. In addition, it is also difficult to modulate the pharmacodynamic and pharmacokinetic characteristics of such formulations in vivo. Therefore a continuing need exists for novel, stable and nontoxic formulations and compositions for the delivery of hydrophobic drugs.
The present application describes a composition that utilizes a biocompatible matrix (hydrophilic or hydrophobic) containing a solid form of bioactive agent dispersed in it. Depending on the size (surface) of the bioactive agent particles and the nature of the polymeric matrix (i.e. hydrogel, elastomer, solid polymer, hydratable dry polymer, and biodegradation properties) the rate of said bioactive agent release and duration of the release in vivo may be modulated in much wider range than currently know in the art. In one aspect, the formulations described in this application enable new safer therapeutic products for clinical use.